Project Summary There is increasing interest in the development of covalent ligands of proteins, which have many advantages over non-covalent ligands. The goal of this proposal is to develop large libraries of DNA-encoded libraries of potential covalent ligands and to optimize methods to screen them. This would represent a major advance over current technology to identify covalent ligands, which almost always relies on structure-aided grafting of an electrophile onto an existing reversible ligand. The successful completion of this Phase I effort would establish a platform that Deluge could offer customers in the form of a custom screening service for the identification of potent and selective covalent ligands for any protein of interest to the customer that has surface-accessible cysteines.